A Novel Dual Bruton's Tyrosine Kinase/Janus Kinase 3 Inhibitor Wj1113 and its Therapeutic Effects on Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and tissue damage, driven by dysregulated cytokine signaling and immune cell hyperactivation. Bruton's tyrosine kinase (BTK) mediates pathogenic B-cell activation and autoantibody production, while Janus kinase 3 (JAK3) orchestrates cytokine-driven inflammation through signal transducer and activator of transcription 5 (STAT5) phosphorylation, exacerbating macrophage and monocyte activation. Here, we report Wj1113, a novel dual inhibitor that potently blocks BTK (IC₅₀ = 0.7 nM) and JAK3 (IC₅₀ = 26.2 nM). Wj1113 inhibits B-cell activation via BTK blockade and suppresses JAK3-dependent STAT5 phosphorylation, reducing proinflammatory cytokine secretion and monocyte chemotaxis. In vitro, it suppresses macrophage activation and modulates inflammatory mediator expression. In the collagen-induced arthritis mouse model, Wj1113 treatment dose-dependently reduces joint inflammation, macrophage infiltration, and levels of TNF-α (tumor necrosis factor-α), IL(interleukin)-6, anti-cyclic citrullinated peptide antibody (ACPA) and rheumatoid factor (RF), while elevating anti-inflammatory IL-10. Histopathological and micro-CT analyses confirm attenuation of cartilage/bone erosion and synovial hyperplasia. Mechanistically, Wj1113 inhibits BTK/JAK3 signaling in vivo and alleviates arthritis in joints. Collectively, these findings establish Wj1113 as a promising dual-target therapeutic candidate for RA, addressing both B-cell and cytokine-driven pathogenic pathways.